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BACKGROUND: A set of enduring conditions have been reported in the literature involving persistent sexual dysfunction after discontinuation of serotonin reuptake inhibiting antidepressants, 5 alpha-reductase inhibitors and isotretinoin.OBJECTIVE: To develop diagnostic criteria for post-SSRI sexual dysfunction (PSSD), persistent genital arousal disorder (PGAD) following serotonin reuptake inhibitors, post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD).METHODS: The original draft was designed using data from two published case series (Hogan et al., 2014 and Healy et al., 2018), which represent the largest public collections of data on these enduring conditions. It was further developed with the involvement of a multidisciplinary panel of experts.RESULTS: A set of criteria were agreed upon for each of the above conditions. Features of PSSD, PFS and PRSD commonly include decreased genital and orgasmic sensation, decreased sexual desire and erectile dysfunction. Ancillary non-sexual symptoms vary depending on the specific condition but can include emotional blunting and cognitive impairment. PGAD presents with an almost mirror image of unwanted sensations of genital arousal or irritability in the absence of sexual desire. A new term, post-SSRI asexuality, is introduced to describe a dampening of sexual interest and pleasure resulting from a pre-natal or pre-teen exposure to a serotonin reuptake inhibitor.CONCLUSIONS: These criteria will help in both clinical and research settings. As with all criteria, they will likely need modification in the light of developments.

To develop a reliable 2-compartment population pharmacokinetic (PK) model for unbound ceftriaxone in a critically ill population and determine an optimal dosing regimen.This was a prospective, single-center, observational study of critically ill patients treated with ceftriaxone. Unbound serum ceftriaxone concentrations were measured using validated ultrafiltration and ultra-performance liquid chromatography-tandem mass spectrometry. PK analysis and dosing simulations were performed using an iterative 2-stage Bayesian fitting procedure and Monte Carlo simulations. The PK/pharmacodynamics (PD) target was attained when unbound serum ceftriaxone concentrations exceeded 4 times the minimum inhibitory concentration (MIC) for ≥ 60% of the dosing interval (ƒT91 patients were enrolled, and 173 unbound ceftriaxone concentrations were acquired. The population PK parameter estimates were hepatic clearance 5.2 ± 0.9 L/h/1.85mWe developed a reliable population PK model for unbound ceftriaxone in a critically ill population. Dosing simulations revealed ƒT

Objectives To study the effects of running with/without the use of pain killers on urinary neutrophil gelatinase-associated lipocalin (uNGAL) and other parameters of kidney function in recreational runners. Methods Participants of the 10- and 21.1-km Weir Venloop race were enrolled and their urine samples collected before and after the run. Urine dipstick and other conventional tests used to assess kidney function were performed. The presence of ibuprofen, diclofenac, naproxen, and/or paracetamol was assessed by LC-MS/MS. uNGAL was measured with a two-step chemiluminescent immunoassay. Results NSAIDs/analgesics were detected in urine of 5 (14.4%) 10-km runners and 13 (28.9%) 21.1-km runners. Only half-marathon participants showed significant increases in uNGAL (pre: 11.7 [7.1-34.3] ng/mL; post: 33.4 [17.4-50.4] ng/mL;P = .0038). There was a significant effect of NSAID/analgesic use on uNGAL increase (F-2,F- 76 = 4.210,P = .004). Post hoc tests revealed that uNGAL increased significantly in runners who tested positive for ibuprofen/naproxen compared to runners who did not use any medications (P = .045) or those who tested positive for paracetamol (P = .033). Running distance had a significant influence on the increase in uNGAL (F-1,F- 53 = 4.741,P

Objective: Low-molecular-weight heparins are frequently used to prevent venous thromboembolism. Vasopressor therapy may be associated with inadequate anti-factor Xa activity, thereby increasing the risk of venous thromboembolism. We aimed to assess the association between anti-factor Xa activity and norepinephrine dose in intensive care unit (ICU) patients treated with subcutaneous dalteparin for venous thromboembolism prophylaxis. Materials and methods: This was a prospective observational pilot study in adult ICU patients treated with dalteparin 5,000 RJ subcutaneously once daily and norepinephrine > 0.25 mu g/kg/min. Peak anti-factor Xa activity was monitored and dalteparin doses were adjusted following a predefined dose algorithm. Results: From November 2016 to April 2018, 32 patients were included. No correlation was found between norepinephrine dose and anti-factor Xa activity (r = -0.01, 95% confidence interval = -0.47 - 0.27, p = 0.57). Furthermore, following daltcparin 5,000 RI once daily, 28% of the patients showed anti-factor Xa activity < 0.10 IU/mL. Higher body mass index (BM1) (p < 0.001) but not patients' norepinephrine dose, age, or serum creatinine were risk factors for anti-factor Xa activity < 0.10 IU/mL. Dose increments to 7,500 IU once daily resulted in anti-factor Xa activity >= 0.10 IU/mL in all 5 patients (p = 0.043). Conclusion: In this cohort of ICU patients, no association was found between norepinephrine dose and anti-factor Xa activity following subcutaneous dalteparin 5,000-RJ administration once daily. Furthermore, nearly one-third of the patients showed anti-factor Xa activity below the target concentration for venous thromboembolism prophylaxis. Higher BMI was an independent risk factor for reduced anti-Xa activity.

A 35-year-old man with generalized insults was admitted to the intensive care unit because of third-line treatment of persistent epileptic insults with antiepileptic drug therapy. Topiramate was added on top of his outpatient regimen in combination with intravenous antiepileptic drugs. Miscommunication and inappropriate topiramate dosing (2,500 mg twice) resulted in an acute topiramate intoxication. Toxicokinetic assessment showed toxic serum topiramate concentration of 55 mg/L and a dose-dependent shift of peak time t(max). According to our modulations, t(max) follows Y = 0.0009X + 2.65, where X is the topiramate dose. Our results have important implications for effectiveness of gut decontamination modalities.

Phenotype Prediction Scores (PPS) might be powerful tools to predict traits or the efficacy of treatments based on combinations of Single-Nucleotide Polymorphism (SNPs) in large samples. We developed a novel method to produce PPS models for small samples sizes. The set of SNPs is first filtered on those known to be relevant in biological pathways involved in a clinical condition, and then further filtered repeatedly in a survival strategy to select stabile positive/negative risk alleles. This method is applied on Female Sexual Interest/Arousal Disorder (FSIAD), for which two subtypes has been proposed: 1) a relatively insensitive excitatory system in the brain for sexual cues, and 2) a dysfunctional activation of brain mechanisms for sexual inhibition. A double-blind, randomized, placebo-controlled cross-over experiment was conducted on 129 women with FSIAD. The women received three different on-demand drug-combination treatments during 3 two-week periods: testosterone (0.5 mg) + sildenafil (50 mg), testosterone (0.5 mg) + buspirone (10 mg), or matching placebos. The resulted PPS were independently validated on patient-level and group-level. The AUC scores for T+S of the derivation set was 0.867 (95% CI = 0.796–0.939; p

Background: Ceftriaxone is recommended for empiric antimicrobial therapy in patients with sepsis. Therapeutic Drug Monitoring (TDM) guided dose optimisation could elucidate pharmacokinetic variabilities, improving treatment efficacy. However, detailed data on Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) for unbound ceftriaxone quantification in serum are scarce. Objective: The authors aimed to develop a reliable UPLC-MS/MS method for serum ceftriaxone quantification and exhibit its application potential in routine hospital settings. Methods: In this observational, single centre study, UPLC-MS/MS method validation included specificity, carry-over, linearity, repeatability, intermediate precision, accuracy, the limit of quantification, and plasma protein binding. Unbound and total ceftriaxone were quantified in the serum of 5 critically ill patients. Pharmacokinetic/Pharmacodynamic (PK/PD) target attainment calculations were performed for both unbound and total ceftriaxone. The PK/PD target for unbound ceftriaxone in serum was set at 4 times the non-species related minimum inhibitory concentration breakpoint of 1 mg/L for at least 60% of the dosing interval. Result: The UPLC-MS/MS method revealed acceptable limits for clinical samples, with coefficients of variation Conclusion: The described UPLC-MS/MS method enables reliable and rapid ceftriaxone quantification in the serum of critically ill patients. Method feasibility was exhibited for TDM purposes in routine clinical practice.

Contains fulltext : 227505.pdf (Publisher’s version ) (Open Access) Histamine is involved in various physiological functions like sleep-wake cycle and stress regulation. The histamine N-methyltransferase (HNMT) enzyme is the only pathway for termination of histamine neurotransmission in the central nervous system. Experiments with HNMT knockout mice generated aggressive behaviours and dysregulation of sleep-wake cycles. Recently, seven members of two unrelated consanguineous families have been reported in whom two different missense HNMT mutations were identified. All showed severe intellectual disability, delayed speech development and mild regression from the age of 5 years without, however, any dysmorphisms or congenital abnormality. A diagnosis of mental retardation, autosomal recessive 51 was made. Here, we describe a severely mentally retarded adolescent male born from second cousins with a homozygous mutation in HNMT. His phenotypic profile comprised aggression, delayed speech, autism, sleep disturbances and gastro-intestinal problems. At early age, regression occurred. Treatment with hydroxyzine combined with a histamine-restricted diet resulted in significant general improvement. 4 p.

Background Pharmacokinetic studies of cefuroxime by ultra‐performance liquid chromatography tandem mass spectrometry (UPLC‐MS/MS) have been limited to measurements of total concentrations. Here, we developed a robust method for quantifying total and unbound cefuroxime concentrations using UPLC‐MS/MS and ultrafiltration in critically ill patients with hypoalbuminemia and renal failure. Methods Method validation included accuracy, linearity, precision, repeatability, recovery, and limit of quantification (LOQ). Feasibility of the method was performed on samples obtained from randomly selected intensive care unit (ICU) patients. Total and unbound cefuroxime concentrations were quantified using UPLC‐MS/MS. Sampling times were categorized as trough (180‐1 min prior to administration), peak (10‐30 min after administration), mid (30‐360 min after administration), and continuous (sampling during administration). Pharmacokinetic/pharmacodynamic (PK/PD) targets were unbound cefuroxime concentrations above 4 times the minimum inhibitory concentration (32 mg/L). Results Intra‐assay and inter‐assay precision was

Men with Subjective premature ejaculation (PE) have complaints of PE but have normal intravaginal ejaculation latency time (IELT) durations. We found two previously published large epidemiological stopwatch-mediated IELT studies to encompass IELT details of men with Subjective PE, albeit this term was not mentioned in both studies or in reviews of them. In the current study we developed the mathematical formula of the IELT distribution of men with complaints of PE, as diagnosed by a clinician on basis of the DSM-IV-TR definition of PE, as reported in the two studies performed in the USA and Europe, respectively. The formula was calculated by investigation of the fitness of various well-known mathematical Probability Density distributions into the IELT distribution of the PE men and non-PE men of the two studies. The better the fitness the lower is the Goodnes of Fit (GOF). Another aim of the study was to investigate whether the IELT distribution of men with "complaints" of PE (Subjective PE) differs mathematically from the IELT distribution of the general male population and that of Lifelong PE. The overlap of the area under the curve (AUC) of the IELT distribution of the men with PE complaints and that of the general male population was calculated together with the cut-off point at which the AUC equals 10%. We found that the IELT distributions of the PE men in both studies were Lognormal distributions and that at the cut-off point at which the AUC is equal to 10% (p = 0.10) the IELT is 1.5 min, indicating that after 1.5 min the IELT distribution of males with complaints of PE becomes mathematically identical to that of the general male population. In conclusion, there is hard mathematical evidence that the IELT distribution of men with complaints of PE with normal IELT values (e.g., the Lognormal IELT distribution of Subjective PE) and the IELT distribution of men with Lifelong PE (e.g. the Gumbel Max IELT distribution) belong to two independent populations. According to the applied mathematical calculations Subjective PE starts after an IELT of 1.5 min and encompasses all higher IELT values. It may imply that the current IELT cut-off point in Lifelong PE should be 1.5 min instead of the approximate 1 min, as has previously been stated by ISSM and DSM 5.

Recently it was shown that a stopwatch-measured IELT distribution can be transformed to a mathematical formula of a specific mathematical type distribution. The IELT distribution of men in the general population is a Lognormal distribution whereas that of Caucasian men with lifelong premature ejaculation (PE) is a Gumbel Max distribution. In this article, we developed the mathematical formula of the IELT distribution of two other previously published stopwatch-mediated IELT studies in the general male population of the USA and Europe, respectively, by investigating the fitness of various well-known mathematical probability density distributions into the IELT distribution of the two studies. The better the fitness the lower is the goodnes of fit (GOF). We found that the lognormal distribution most accurately fitted the IELT distribution of 1405 men in the general population of the USA, and 1026 men in the general population of Europe, with a GOF of 0.056 and 0.061, respectively. The current study also shows that the Lognormal IELT distribution of two European studies in Caucasian males are quite similar but that the Lognormal IELT distribution of men in the USA deviates compared to the two European IELT distributions. As the USA study also included 25% of non-Caucasian males it may be speculated that ethnical factors play a role in this deviation of the IELT curve. In conclusion, the Lognormal distribution of the IELT distribution in USA and European general male populations reconfirms our previous finding of a Lognormal IELT distribution in two random samples of the general male population in four European countries and USA. The Lognormal IELT distributions of the general male population highly contrasts to the Gumbel Max IELT distribution in Caucasian males with lifelong PE, as has previously been found.

In the present issue of Investigative and Clinical Urology, Janssen and Waldinger [1] publish an important mathematical contribution on the intravaginal ejaculatory latency time (IELT) distributions of men in the general adult population compared to the IELT distribution of men with lifelong premature ejaculation (PE). Data used to study these distributions were derived from earlier studies on Caucasian males in Europe and North America. Although both populations (normal and lifelong PE) are small due to the experimental design with stopwatch methodology, the authors have convincing and valid arguments that both populations have distinct mathematical IELT distributions. This leads to interesting consequences, hypotheses and research possibilities. Lifelong PE has convincingly been shown to be a very stable putative endophenotype within the range of all IELT's measured all over the world in different populations and cultures [2]. This stability strongly suggests that this endophenotype is caused by underlying biological mechanisms, presumably anchored in the central nervous system. The mathematical different distribution models of the IELT in the general population and lifelong PE males furthermore strongly supports biological differences underlying these IELT distributions and argues against psychological or behavioral interventions aimed at elongation of the IELTs in PE males. Whether such biological and fundamental different processes in the IELT of lifelong PE can be considered as 'pathological' remains a tricky question. As long as men present their PE as an unwished phenomenon from which they and their partner suffer and look for help, PE can be considered as pathological and deserves treatment if possible. Further studies into the underlying mechanisms of life long PE is urgently needed as the only efficient treatment of PE so far are the SSRI. Apart from their side effects, SSRIs have to be taken daily and life long, i.e., as long as a wish for a 'normal' sex life exists. Ideally, an 'on demand' treatment should be used, but the existing SSRI's, including dapoxetine as an approved 'on-demand' prescription drug for PE, hardly fulfill such claims [3]. Much more fundamental insight into the brain and spinal cord mechanisms involved in sexual behavior and ejaculatory processes are needed to possibly develop new pharmacological approaches to better treatment of lifelong PE. Several strategies have to be developed and applied, in particular genetic, genomic and epigenetic approaches and techniques have to be implemented. The biological hardware differences in IELT between the normal and abnormal (lifelong PE) populations and the high familiar occurrence of PE [4] suggest that genetic technology (e.g., GWAS and expression studies) might help to identify factors (e.g., functional SNPs) that are involved. Moreover, central nervous system (CNS) functional magnetic resonance imaging studies (including spinal cord imaging) comparing normal IELT with lifelong PE men, where males are challenged with various sexual stimuli (visual, tactile) might unravel or differentiate activity (or lack of) in brain/spinal cord areas that generate new ideas and hypotheses on brain mechanisms involved. Similarly, comparison of SSRI-treated (by preference chronically treated) males with normal IELT and lifelong PE males using brain/spinal cord imaging might further contribute to understanding of the mechanisms and brain localizations of the SSRI-induced changes in focal areas. Fundamental results from such brain studies in untreated and SSRI-treated populations might also generate hypotheses that can be used in a translational way in animal models of sexual behavior and sexual dysfunctions. The serotonergic (5-HT) system seems an extremely important neurotransmitter system in the modulation of sexual behavior including ejaculatory processes [5]. Most research into this topic derives from animal studies, but the translational prediction of rat models of ejaculatory speed for human ejaculation latencies (IELT) appears rather high [6]. In general, increased 5-HT levels in the CNS elevate ejaculatory thresholds probably via activation of 5-HT1B and 5-HT2C receptors, whereas 5-HT depletion decreases the ejaculatory threshold. 5-HT1A receptor activation strongly facilitates ejaculatory processes, either mediated by lowering 5-HT levels via activation of presynaptic (somatodendritic) 5-HT1A autoreceptors and/or stimulation of postsynaptic 5-HT1A heteroreceptors. We found that concurrent treatment of SSRIs and a silent 5-HT1A receptor antagonist, strongly facilitated the inhibiting effects of SSRIs on male ejaculation [6], both after acute and chronic dosing. This suggests a new approach to an 'on-demand' treatment of PE; acute SSRI administration (e.g., paroxetine or escitalopram) plus a 5-HT1A receptor antagonist (e.g., pindolol, a relative weak 5-HT1A receptor antagonist and a β-adrenoceptor antagonist-with the intrinsic risk of cardiovascular side effects). Safarinejad [7] used a high dose of pindolol (7.5 mg/d) for 6 weeks to men with PE who were refractory to paroxetine (20 mg/d) treatment for at least 2 months. Pindolol had a slight facilitating effect on PE in these paroxetinetreated men over the 6 weeks treatment. Although in this case pindolol appears a mild augmentation strategy in paroxetine-refractory patients, the data suggest that pindolol exerts its effects via blockade of 5-HT1A receptors interfering with the SSRI-induced enhancement of overall 5-HT neurotransmission. Further support for an important role of the 5-HT1A receptor in the inhibitory action of SSRIs on sexual behavior and ejaculation, in depression treatment considered as unwanted side effect, comes from findings with vilazodone in sexual behavior. Vilazodone exerts blockade of the serotonin transporter (SERT) concomitant with 5-HT1A receptor agonistic activity. In a rat model of measuring sexual side effects, vilazodone has no inhibitory effects on male sexual behaviors after acute or chronic treatment, whereas paroxetine or citalopram, SSRI, had strong inhibitory effects [8]. This suggests that vilazodone is probably not very (or not at all) effective in lifelong PE, but a potential attractive antidepressant/anxiolytic with no or less sexual side effects. The serotonergic system in the brain is a complex, extremely ramified system emerging in the raphe nuclei in the midbrain and projecting to practically all areas of the brain and spinal cord [3]. The 5-HT complex (in)directly interacts with all neurotransmitter systems in the CNS via 14 different postsynaptic (hetero) receptors and presynaptic autoreceptors; the serotonin transporter (SERT or 5-HTT) is the main regulatory mechanism in the modulation of the serotonergic tone via uptake of released 5-HT, thereby terminating 5-HT-ergic stimulation [3]. The SERT is the target of SSRI's that are known to delay ejaculation. Having a high affinity for 5-HT, the SERT controls the duration, availability and signaling capacity of synaptic 5-HT and therefore might determine the speed of ejaculation. If SERT activity is high, serotonergic neurotransmission is low(er) and this seems associated with a short IELT (5-HT functions as a brake on ejaculation). The 5-HTT functioning is moderated by a polymorphism in the 5-HTT promoter region of the SERT gene (SCL6A4) which encodes for the SERT protein (5-HT transporter-linked promoter region: 5-HTTLPR). The latter has a short (S) and a long (L) variant allele associated with low (S) and high (L) transcriptional activity. Thus, SS genotypes have much lower SERT activity than LL genotypes (SL are intermediate) and it has been postulated that men with SS genotype have longer IELT durations than men with LL genotypes. This was confirmed in a population of men with life long PE [9]. This is indeed a remarkable finding because in a population with already extremely short ejaculation latencies, a functional polymorphism (LL) was associated with a reduction of IELT of 50%. Data in the normal population are lacking, but a comparable pattern might be expected. An important remark, however, is that the promoter length polymorphism in the SERT gene cannot be the genetic base for lifelong PE but only a modulatory factor [9]. Moreover, the ejaculatory process itself is not critically dependent on the serotonergic system; it seems logical to postulate that many other neurotransmitter systems in the CNS contribute to the complex ejaculatory process although much research is needed to unravel the complex processes involved [3]. In conclusion: the finding by Janssen and Waldinger [1] that the ejaculatory process in lifelong PE essentially differs from that in normal ejaculating males, strongly indicates that PE can be considered as a dysfunction of the ejaculatory process. Future studies have to support this finding and might lead to new ideas about PE and possibly new treatments.

Attempts to develop a drug treatment for female sexual interest/arousal disorder have so far been guided by the principle of ‘one size fits all’, and have failed to acknowledge the complexity of female sexuality. Guided by personalized medicine, we designed two on-demand drugs targeting two distinct hypothesized causal mechanisms for this sexual disorder. The objective of this study was to design and test a novel procedure, based on genotyping, that predicts which of the two on-demand drugs will yield a positive treatment response. In a double-blind, randomized, placebo-controlled cross-over experiment, 139 women with female sexual interest/arousal disorder received three different on-demand drug-combination treatments during three 2-week periods: testosterone 0.5 mg + sildenafil 50 mg, testosterone 0.5 mg + buspirone 10 mg, and matching placebo. The primary endpoint was change in satisfactory sexual events. Subjects’ genetic profile was assessed using a microarray chip that measures 300,000 single-nucleotide polymorphisms. A preselection of single-nucleotide polymorphisms associated with genes that are shown to be involved in sexual behaviour were combined into a Phenotype Prediction Score. The Phenotype Prediction Score demarcation formula was developed and subsequently validated on separate data sets. Prediction of drug-responders with the Phenotype Prediction Score demarcation formula gave large effect sizes (d = 0.66 through 1.06) in the true drug-responders, and medium effect sizes (d = 0.51 and d = 0.47) in all patients (including identified double, and non-responders). Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the Phenotype Prediction Score demarcation formula were all between 0.78 and 0.79, and thus sufficient. The resulting Phenotype Prediction Score was validated and shown to effectively and reliably predict which women would benefit from which on-demand drug, and could therefore also be useful in clinical practice, as a companion diagnostic establishing the way to a true personalized medicine approach.

Background: Cefuroxime is frequently prescribed as an antimicrobial therapy in critically ill patients. The aim of this study was to develop a new intravenous dosing strategy for cefuroxime in critically ill patients undergoing continuous venovenous hemofiltration with regional citrate anticoagulation (RCA-CVVH) by analyzing its extracorporeal removal and pharmacokinetic (PK) parameters. Methods: Nine critically ill patients treated with intravenous cefuroxime and RCA-CVVH and a phosphate-containing replacement fluid were investigated. Arterial and effluent samples were obtained from all patients and pre-and postfilter venous blood samples were obtained from a subgroup of 5 patients. Plasma cefuroxime levels were determined by ultraperformance liquid chromatography-mass spectrometry in plasma samples collected before and after intravenous infusion of either 1500 mg cefuroxime every 12 hours or 3000 mg continuously over 24 hours. Population PK analysis and dosing simulations were performed using nonlinear mixed-effects modeling and Monte Carlo simulations. Results: The volume of distribution (VD) of cefuroxime in the central compartment, corrected for lean body mass, was 0.11 +/- 0.056 L/kgLBMc, CVVH-mediated clearance was 49.5-50.6 mL/min, the mean elimination half-life (t(1/2)) was 90 minutes (77-103), and the mean sieving coefficient was 0.89 +/- 0.01. A 2-compartment model with between-subject variability in clearance, V-D, and t(1/2) described these data adequately. Simulation of a standard dosing regimen (750 mg/12 hours) predicted failure to achieve the international target plasma cefuroxime concentration (32 mg/L). Conclusions: Cefuroxime clearance by RCA-CVVH was twice the reported clearance during standard CVVH. Our PK data predicted that a maintenance dose of 3000 mg cefuroxime, infused over 24 hours, would provide an optimal steady-state plasma concentration of 38.5 mg/L. The developed population PK model for cefuroxime has the potential to inform new dosing schedules in patients receiving cefuroxime during RCA-CVVH.